PROJECT SUMMARY Chronic rhinosinusitis (CRS) is one of the most prevalent inflammatory diseases in the U.S., affecting up to 16% of the population and substantially diminishing the quality of life and productivity of patients. In four years, the annual U.S. health care expenditure to treat patients with CRS dramatically increased from $9B to $64B (5% of the health care budget), with a corresponding rise in surgical treatment for those 20% of patients who fail current medical management. Despite these staggering statistics, CRS remains an under-researched epidemic with limited effective treatment options. GlycoMira?s lead candidate, GM-1111, is a synthetic glycosaminoglycan that inhibits multiple inflammatory mediators and more specifically, targets Toll-like receptor 2-mediated signaling. Moreover, topical intranasal administration of GM-1111 effectively reduces chronic sinonasal inflammation in mice. Animals treated with GM-1111 showed significant reductions in degenerative histologic changes, inflammatory cell infiltration, goblet cell hyperplasia, and cytokine gene expression within the sinonasal tissues. Herein, GM-1111 will be further developed and validated as a commercially viable and effective therapy for CRS. In Aim 1, the optimal dosing regimen and degree to which GM-1111 effectively treats CRS will be determined by testing a wide range of doses and dosing frequencies in animal models of CRS. The efficacy of GM-1111 will be compared to healthy, inflammatory, and therapeutic controls by analyzing the clinical signs, histologic changes, and inflammatory tissue biomarkers associated with CRS. In Aim 2, the potential mucolytic properties of GM-1111 will be investigated, and the effect of GM-1111 on ciliary function will be determined. Increased mucus production and impaired mucociliary clearance are central to the pathogenesis of CRS and elevate the risk of opportunistic pathogen infection. Based on mechanistic evidence with a similar glycosaminoglycan, topically administered GM-1111 should penetrate mucus and reduce sinonasal inflammation. To test this hypothesis, the effects of GM-1111 on artificial mucus with known mucin and bacterial composition, nasal secretions from patients with CRS, and ciliary function using sinonasal tissue from controls and patients with CRS will be investigated. The efficiency of GM-1111 to penetrate mucus and tissue to effectively reduce sinonasal inflammation will then be determined in an animal model of CRS characterized by a robust mucus response. These studies will provide crucial preclinical data supporting GM- 1111 as a commercially viable and effective therapeutic for treating the millions of patients affected by this debilitating disease.